Transcript the inclusion complexes of furosemide β-cd

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New complexes
of inhaled
Furosemide
and Cyclodextrin:
Assessment of the
bronchodilator effect
Ramadan Al-Shdefat, Ph.D
Pharmaceutics Department
College of Pharmacy
Prince Sattam Bin Abdulaziz University
Saudi Arabia
OUTLINE
 Introduction
 Methods
 Results
 Conclusions
Free Powerpoint Templates
Introduction
• Furosemide, a loop diuretic, is practically
insoluble in water (0.01825 mg/mL) and is
degraded by light1,2.
• The bioavailability of orally administered
furosemide in conventional dosage forms is poor
and highly variable, and associated with low
aqueous solubility, site-specific drug absorption,
and first-pass metabolism3.
• Some studies showed that inhalation of furosemide
alleviates dyspnoea by modulating vagal afferent
activity in animal lung models4 and reduces the
intensity of induced dyspnoea in healthy individuals 5.
• Further studies suggested that nebulised furosemide
might be effective against dyspnoea of asthma6 and
lung cancer 7.
• β-cyclodextrin (β-CD) is a natural cyclic
oligosaccharide and several studies have reported
a positive effect of CD complexation on the
physicochemical
characteristics
of
many
hydrophobic drugs8.
Cyclodextrins contain 6, 7 or 8 dextrose molecules
(α, β, γ-cyclodextrin) bound in a 1,4- configuration
to form rings of various diameters.
• The ring has a hydrophilic exterior and lipophilic
core in which appropriately sized organic molecules
can form non-covalent inclusion complexes.
• Complexation relies on relatively weak force such as
London
forces,
hydrogen
bonding
and
hydrophobic interactions.
• Inclusion complexation with agents such as βcyclodextrin (β-CD) is one method to increase
the aqueous solubility of a poorly water-soluble
drug and thereby its stability and bioavailability9.
Nature Reviews Drug Discovery
Aim of the Study
The objective of this study was to investigate the
efficacy of nebulised furosemide administered
singly or in combination with β-cyclodextrins (βCDs) on asthma exacerbations in children .
METHODS
Drugs

The inclusion complexes of furosemide/βCD in 1:1 and 1:0.5 molar ratios were
prepared using the kneading technique,
which is a simple, common and inexpensive
method for preparing inclusion complexes.
THE INCLUSION COMPLEXES OF FUROSEMIDE Β-CD PREPARATION
THE INCLUSION COMPLEXES OF FUROSEMIDE Β-CD PREPARATION
THE INCLUSION COMPLEXES OF FUROSEMIDE Β-CD PREPARATION
THE INCLUSION COMPLEXES OF FUROSEMIDE Β-CD PREPARATION
THE INCLUSION COMPLEXES OF FUROSEMIDE Β-CD PREPARATION
THE INCLUSION COMPLEXES OF FUROSEMIDE Β-CD PREPARATION
THE INCLUSION COMPLEXES OF FUROSEMIDE Β-CD PREPARATION
THE INCLUSION COMPLEXES OF FUROSEMIDE Β-CD PREPARATION
THE INCLUSION COMPLEXES OF FUROSEMIDE Β-CD PREPARATION
THE INCLUSION COMPLEXES OF FUROSEMIDE Β-CD PREPARATION
The study was a single-blinded
controlled randomised trial, involving
five groups of children
All drugs were dissolved in 4 mL normal saline before use
in the nebulisation chamber.
Nebulisation was continued for 20 min until the
nebulisation chamber was empty.
Pulmonary function was assessed by measuring:
(FEV1) forced expiratory volume in 1 s; (FVC) forced vital
capacity; (PFER) peak expiratory flow rate; (RR)
respiratory rate; (SaO2) arterial oxygen saturation
in each patient before and 30 min after medication.
Nebulized Salbutamol
20
Nebulized Furosemide
15
Salbutamol plus
Furosemide
10
Frosemide/β-CD (1:0.5)
5
Furosemide/β-CD (1:1)
% of changes from baseline (Mean)
25
0
Pulmonary Function Parameters
 Complexes
of furosemide and CD improve
FEV1, FVC, peak flow rate, SaO2 and clinical
scores significantly as compared to salbutamol
or furosemide alone. The complex effect was
nearly equal to the effect of the furosemide
and salbutamol combination.
 These
results suggest that CDs are promising
solubility enhancers for improving the
efficacy of poorly water-soluble drugs
administered by inhalation.
REFERENCES
1)
Shin S-C, Kim J. Physicochemical characterization of solid dispersion of furosemide with TPGS. Int J Pharm
2003;251:79–84.
2)
Yahya A, McElnay J, D’Arcy P. Photodegradation of frusemide during storage in burette administration sets.
Int J Pharm 1986;31:65–8.
3)
Ponto LL, Schoenwald RD. Furosemide (frusemide). A pharmacokinetic/pharmacodynamic review (Part I).
Clin Pharmacokinet 1990;18:381–408.
4)
Sudo T, Hayashi F, Nishino T. Responses of tracheobronchial receptors to inhaled furosemide in
anesthetized rats. Am J Respir Crit Care Med 2000;162:971–5.
5)
Nishino T, Ide T, Sudo T, et al. Inhaled furosemide greatly alleviates the sensation of experimentally induced
dyspnea. Am J Respir Crit Care Med 2000;161:1963–7.
6)
Rodríguez Vázquez JC, Pino Alfonso PP, Gassiot Nuño C, et al. Assessment of the bronchodilator effect of
inhaled furosemide compared to salbutamol in asthmatic patients. J Investig Allergol Clin Immunol; 8:115–
8.
7)
Kohara H, Ueoka H, Aoe K, et al. Effect of nebulized furosemide in terminally illcancer patients with
dyspnea. J Pain Symptom Manage 2003;26:962–7.
8)
Dos Santos C, Buera MP, Mazzobre MF. Phase solubility studies and stability of cholesterol/β-cyclodextrin
inclusion complexes. J Sci Food Agric 2011;91:2551–7.
9)
Miyake K, Arima H, Hirayama F, et al. Improvement of solubility and oral bioavailability of rutin by
complexation with 2-hydroxypropyl-beta-cyclodextrin. Pharm Dev Technol 2000;5:399–407.
Patients
Children were diagnosed as having asthma according to the American
Thoracic Society criteria.
Their characteristics are given in table 1.
The inclusion criteria were:
 Mild or moderate asthma exacerbation with a clinical asthma
 score (CAS) of between 1 and 6.
 Age between 6 and 18 years.
 Ability to perform a peak flow meter test.

Pulmonary function was assessed by measuring
forced vital capacity (FVC) and forced expiratory
volume in 1 s (FEV1) with a computerised wedge
spirometer in each patient before and 30 min after
medication.

Flow rates were measured using a Mini Wright peak
flow meter.

Furosemide may interfere with the transport of ions
such as Na+, Cl− and K+ via the mucous epithelium,
changing the osmolality of secretions and
simultaneously modifying bronchial reactivity. Thus
furosemide may have a relaxing effect on smooth
muscles.

Another explanation is that furosemide may reduce
airway resistance and improve pulmonary
distensibility by blocking the release of secondary
constrictor mediators such as histamine or
leukotrienes, leading to an increase in the exchange
of gases.
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